This Research Plan is submitted in response to the RFA DK-06-504 for the purposes of continuing our role as a Genetic Research Center (GRC) of the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC). This application will discuss the components of the individual GRC located at Yale University. The central goal of this Consortium is to identify susceptibility genes contributing to the pathogenesis of IBD. This plan will refer to the proposal of the DCC of the IBDGC and this GRC proposal should be evaluated in conjunction with the Master Application of the DCC. The showpiece of the first funding period has been the identification of IL23R (interleukin 23 receptor) as a major susceptibility gene for IBD. Multiple association signals within the IL23R gene have been identified, notably an uncommon coding region variant, Arg381Gln, which confers highly significant protection against the development of CD and DC. Preliminary identification of functional innate immune system variants to CD in Ashkenazi Jewish cohorts is reported. Preliminary studies demonstrate a protective effect of the toll-like receptor 5 stop variant, TLR5-stop against CD. A polymorphism in the interferon regulatory factor 5 gene, IRF5, that directly results in expression of splice variants and has been associated in lupus, similarly demonstrates association to Jewish CD. Three specific aims are proposed. Specific Aim 1: Expansion, Development and Management of Consortium Resources. We define the operational YUGRC-DCC-IBDGC interface that will assure appropriate prioritization of Consortium resources and recruitment and phenotypic characterization of IBD cases and controls. Specific Aim 2: To employ a variety of approaches to identify genetic variation that contributes to IBD susceptibility. Replication studies testing TLR5-stop and IRF5 variants in future, Jewish CD cases are proposed. Complete characterization of the IL23R gene and pathway is proposed. Nod2 pathway analyses stratified on Nod2 genotypes may provide improved power. Specific Aim 3 To build a risk model of IBD through understanding genetic influence on variations in phenotypic expressivity, gene pathway analysis, and gene-gene (G x G) and gene-environmental (G x E) interactions. Well-powered gene-gene interactions along the Nod2 and IL23R pathways will be examined based on biologic and genetic models.